Project Summary/Abstract The respiratory community has traditionally defined respiratory health as the absence of lung disease. This definition results in early lung disease being defined as the first appearance of abnormal respiratory physiology, a paradigm that does not acknowledge that the transition from health to chronic lung disease develops over years, a period of time when lung disease interception strategies could be most efficacious. A public health strategy for chronic lung disease focused on disease interception mandates the detection of impaired respiratory health before chronic lung disease becomes clinically apparent. Our group has investigated the predictors and consequences of lung function decline in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal cohort aged 18-30 at inception in 1985. We have identified features of impaired respiratory health that precede the development of chronic lung disease. These include: lower peak lung function in young adulthood, accelerated age-related decline in lung function, elevations in systemic inflammatory biomarkers, and the presence of respiratory symptoms. While we have documented the clinical relevance of impaired respiratory health, our work to-date does not provide a set of targets for the interception of chronic lung disease. We now propose to take advantage of CARDIA's unique platform to study the transition from impaired respiratory health to lung disease. In this renewal application to the CARDIA Lung study, we will build upon our work which has determined phenotypes of impaired lung health by collecting lung CT scans, pulmonary function, and nasal epithelial gene expression at the CARDIA year 35 examination. We will seek to validate phenotypes and identify endotypes of impaired respiratory health. We will test the hypothesis that imaging, blood, and nasal biomarkers serve as useful phenotypes and endotypes of impaired lung health and are associated with transitions to chronic lung disease through the following specific aims: (1) Determine multidimensional (integrating both longitudinal measures of lung function and CT lung injury) lifecourse trajectories associated with the future development of emphysema and interstitial change, (2) Using a proteomic discovery-platform, determine whether blood biomarkers predict divergent phenotypic manifestations of lung disease (emphysema vs. interstitial change) in the transition from impaired respiratory health to lung disease, (3) Determine whether CT lung injury, emphysema, and interstitial change are associated with altered gene expression in the nasal respiratory epithelium. This study will investigate factors associated with susceptibility versus resilience to lung disease and the pathobiologic changes associated with impaired lung health, and in doing so, will contribute to a foundation for the future interception of chronic lung disease.